Sunday, August 11, 2019

Cancers Caused by Contagious Agents

We do not generally regard cancer as being contagious. Although this is generally t rue, there are a growing number of cancers that have been shown to be caused by contagious agents, especially by specific viruses. The types of cancers caused by such agents are shown along with the microorganism implicated.

Cancer Causative Agent

Stomach (Gastric) Cancer H. Pylori - Bacterium
Cervical Cancer Human Papilloma Virus (HPV)
T-Cell Leukemia HTLV-1 – related to the AIDS virus
Burkitt’s Lymphoma Epstein Barr Virus (EBV)
Kaposi’s Sarcoma HTLV-3 – AIDS Virus
Primary Liver Cancer Hepatitis B Virus (HBV)

In regards to the data listed in the table above, there is additional information associated with them:

• H.Pylori is a highly specialized and fairly ubiquitous bacterium that can survive in the harsh acidic environment of the stomach; it is found in the mucus layer on the inside of the stomach within those individuals who are infected. For this reason, it is particularly difficult to treat with antibiotics. It is found in about 2/3 of the world’s population. It has also been implicated in the onset of chronic gastritis and peptic ulcers.
• HPV has recently been implicated as the causative agent for cervical cancer. Cervical cancer is prevalent in sexually active women. A vaccine against this virus has recently been developed. It has been shown to be highly effective in preventing the onset of this cancer in young women.
• EBV, the virus that causes Burkitt’s lymphoma found predominantly in Africa, is the same virus that causes mononucleosis in individuals in the West. The reason for this distinct difference in disease outcomes is poorly understood, but a genetic basis for this difference is likely.
• The AIDS virus is not directly responsible for the onset of Kaposi’s sarcoma. The disease is manifested in AIDS patients on account of their highly suppressed immune system due to infection with the AIDS virus that make AIDS patients especially susceptible to this cancer.
• Once an individual is infected with HBV as a result of close human contact with an infected individual, the virus can infect the liver without any noticeable symptoms. This can be the case for many years before the onset of liver cancer. HBV is believed to account for 80% of the reported cases of primary liver cancer (cancer that originates in the liver). It is a deadly cancer. Fortunately, there is a vaccine against HBV infection, but there is currently no vaccine to prevent infection by the Hepatitis C Virus (HCV) that is also known to cause primary liver cancer.

Control of Inflammation following Injury or Infection

The natural immune responses that are elicited after an insult to the body as a result of injury or infection from a pathogen, is both rapid and powerful. Initially inflammatory cells are mobilized to the site of the trauma. The predominant cell types that are recruited are macrophages and neutrophils that release free radical reactive oxygen and nitrogen species (RONS) that are lethal to invading organisms. However, these chemical moieties are so powerful that they can also kill and mutate the surrounding normal tissue. Although there are naturally induced anti-inflammatory responses that are also initiated, the optimum balance is difficult to achieve. In some diseases, such as ulcerative colitis and rheumatoid arthritis, such anti-inflammatory responses are unavailable. Therefore, for this reason medical intervention in the form of medication becomes appropriate. 

There are, of course, many different anti-inflammatory medications currently available. Recently Dr. Torkild Visnes and his colleagues from the Karolinska Institutet in Sweden in collaboration with the University of Texas Medical Branch, Uppsala University and Stockholm University have discovered a new methodology for enhancing the anti-inflammatory response. In order to understand the investigator’s approach, we need to examine the rationale for this research in greater detail. 

Normally the enzyme 8-oxyguanine DNA glycosylase 1 (OGG1) functions as a DNA repair enzyme that both recognizes and repairs the nucleotide base excision repair of 7,8 dihydro-8-oxoguanine (8-oxoG) that represents one of the major types of DNA damage produced by RONS. Paradoxically, the binding of OGG1 to 8-oxoG, facilitates the action of the NF-kB transcription factor that promotes the activation of quiescent chemokine and cytokine genes that subsequently leads to the inflammatory response and the subsequent release of RONS at the site of trauma. 

Visnes and his group have identified a small molecule (TH5487) that binds to the active site of OGG1 and effectively blocks its repair capabilities on account of the fact that inhibited OGG1 cannot bind to that G-rich region of the DNA leads to the activation of the NF-kB transcription factor that promotes proinflammatory genes. In fact, TH5487 has been shown to inhibit this process in mouse and human lung epithelial cells in vitro and the TNF-induced neutrophil inflammation in the in vivo mouse model. 

This research is of value since it elucidates a molecular mechanism that demonstrates a connection between the normal DNA repair function of OGG1 and the inflammatory response and has discovered a small molecule inhibitor of this process.

Saturday, August 10, 2019

A Study in the Evolution of a Transmissible Cancer

There is a canine-related cancer that is sexually transmitted from one animal to another. It is the canine transmissible venereal tumor (CTVT) that presents as genital tumors. It has been shown that this cancer spreads through the transfer of living cancer cells (see image below) through coitus. These CTVT cells function as a unicellular, asexually reproducing (but sexually transmitted) pathogen. In addition, CTVT cells are genetically aberrant in terms of chromosome number – studies have established that instead of the normal 78 chromosomes present in the canine species these cells have a chromosome number in the range of 57-64. This type of cancer represents an exceedingly rare etiology in that the cancer is spread through the transfer of the cancer cell itself.

CTVT Cells
This disease exists worldwide and apparently has the longest known and most prolific evolutionary lineage. This reality provides an opportunity to explore the mechanism of the evolution of cancer over the long term. For this reason, Adrian Baez Ortega, a bioinformatician, and her colleagues from the Transmissible Cancer Group at Cambridge University, UK, have done a detailed analysis of genetic sequence data from 546 individual CTVT tumors taken from diseased animals. Their focus in this analysis was to identify somatic single-nucleotide variants (SNVs) from the exomes – areas of the genetic material that are involved in the active production of proteins. The aim of this intense research study was to help to uncover the mutational events and genetic signatures of the evolutionary selection process over the thousands of years.

One of the predominant findings of this analysis was that this lineage arose from its originator canine individual between 4000 and 8500 years ago most likely from Asia with the most recent ancestor of the current global distribution estimated to have lived about 1900 years ago. There does not appear to be any positive selection for this lineage. In addition, the author of this study concludes that, “a highly context-specific mutational pattern named signature A was identified, which was active in the past but ceased to operate about 1000 years ago. BP, years before present.”

These results provide an insight into the progression of an unusual type of cancer that is transmissible through the transfer of the cancer cell itself rather than through a vector such as a virus – human T Cell Leukemia being one particular example. It also is a demonstration of the power of the widely used tools of research regarding the discovery of the underlying genetic mechanisms involved in disease processes.